Citrulline is a type of amino acids existing in a free state and is not used as a substance of protein synthesis in the body. This compound plays an important role as an arginine precursor in arginine biosynthesis and as a constituting factor of NO cycle associated with NO supply in the body.
NO produced by vascular endothelial cells exhibits a wide range of physiological activities for maintaining normal blood vessel functions such as vascular relaxation, LDL oxidation inhibition, platelet aggregation inhibition, smooth muscle cell antiproliferation, and anti-oxidation. Arteriosclerosis is a symptom that involves loss of elasticity of the vascular wall due to increased inflammatory response in vascular intima and cholesterol accumulation. Such a symptom makes it difficult to maintain a smooth blood flow and promotes formation of blood clots. Many studies indicate a decrease in NO produced by vascular endothelial cells as a cause of this symptom. That is, it can be expected that enhancement of NO production in vascular endothelial cells prevents or ameliorates arteriosclerosis and other ischemic vascular diseases caused by vascular endothelial malfunction and promotes blood flow.
It is reported that citrulline ingestion has an anti-arteriosclerosis effect and a blood flow ameliorating effect mediated by the production of NO which is a vasodilatation factor (Non-Patent Document 1) and citrulline has been used mainly in the United States as a food material for producing NO to ameliorate blood flow. In Europe, citrulline is used as an anti-fatigue drug in the form of citrulline malate.
Serine is one of the nonessential amino acids and plays an important role in a biological function as a constituent element of protein, particularly by existing in the active center of an enzyme. Further, serine is known as a component whose content is the largest among the amino acids contained in natural moisturizing factors for constantly maintaining the water content in the skin.
Heretofore, it has been found that oral administration of serine to mice in which chronic rheumatoid arthritis was induced has an effect of ameliorating the arthritis score (Patent Document 1). Further, it is reported that, the average blood pressure was decreased and the peripheral vascular resistance was decreased in a transient manner (Non-Patent Document 2) by intravenous acute administration of serine to normal rats and spontaneously hypertensive rats (SHR). A study using an NO synthase inhibitor and a calcium-dependent potassium channel inhibitor has revealed that this effect occurs independently of NO by relaxation of vascular smooth muscle through the activation of calcium-dependent potassium channels.
As described above, it has not been known that serine has an effect of promoting NO production and that a synergistic effect of enhancing NO production can be obtained by combining serine and a salt thereof with citrulline or a salt thereof.